Tetrahydronaphthyridinyl-carboxamides having anti-convulsant activity

ABSTRACT

Compounds of formula (I) and pharmaceutically acceptable salts and solvates:  
                 
 
     where R 1  is hydrogen, C 1-6  alkyl (optionally substituted by hydroxy or C 1-4 alkoxy), phenyl-C 1-4 alkyl-, C 1-6 alkenyl, C 1-6 alkynyl;  
     R 2  is hydrogen or up to three substituents selected from halogen, NO 2 , CN, N 3 , CF 3 O—, CF 3 S—, CF 3 CO—, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 perfluoroalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkyl-, C 1-6 alkylO—, C 1-6 alkylCO—, C 3-6 cycloalkylO—, C 3-6 cycloalkylCO—, C 3-6 cycloalkyl-C 1-4 alkylO—, C 3-6 cycloalkyl-C 1-4 alkylCO—, phenyl, phenoxy, benzyloxy, benzoyl, phenyl-C 1-4 alkyl-, C 1-6 alkylS—, C 1-6 alkylSO 2 —, (C 1-4 alkyl) 2 NSO 2 —, (C 1-4 alkyl)NHSO 2 —, (C 1-4 alkyl) 2 NCO—, (C 1-4 alkyl)NHCO— or CONH 2 ;  
     or —NR 5 R 6  where R 5  is hydrogen or C 1-4  alkyl, and  
     R 6  is hydrogen, C 1-4 alkyl, formyl, —CO 2 C 1-4 alkyl or —COC 1-4 alkyl;  
     or two R 2  groups together form a carbocyclic ring that is saturated or unsaturated.  
     R 3  groups and R 4  groups are each independently hydrogen or C 1-6  alkyl and/or the two R 3  groups and/or the two R 4  groups together form a C 3-6  spiroalkyl group, provided that at least one R 3  or R 4  group is not hydrogen; and  
     X is selected from hydrogen, halogen, cyano, alkyl and alkoxy. are useful in the treatment and prophylaxis of epilepsy, migraine, and other disorders.

[0001] This invention relates to novel compounds, to processes forpreparing them, and to their use as therapeutic agents.

[0002] WO97/48683 (SmithKline Beecham) discloses that benzamidecompounds of formula (A) below possess anti-convulsant activity and aretherefore believed to be useful in the treatment and/or prevention ofanxiety, mania, and related depression disorders.

[0003] where n and p are independently integers from 1 to 4 and (n+p) isfrom 2 to 5;

[0004] R¹ is C₁₋₆alkylO—;

[0005] R² is hydrogen, halogen, CN, N₃, trifluoromethyldiazirinyl, CF₃,CF₃O—, CF₃ S—, CF₃CO—, C₁₋₆alkyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkyl-C₁₋₄alkyl-, C₁₋₆alkylO—, C₁₋₆alkylCO—, C₃₋₆cycloalkylCO—,C₃₋₆cycloalkyl-C₁₋₄alkylCO—, phenyl, phenoxy, benzyloxy, benzoyl,phenyl-C₁₋₄alkyl-, C₁₋₆alkylS—, C₁₋₆alkylSO₂—, (C₁₋₄alkyl), NSO₂— or(C₁₋₄alkyl)NHSO₂—;

[0006] R³ is hydrogen, halogen, NO₂, CN, N₃, trifluoromethyldiazirinyl,C₁₋₆ alkylO—, C₁₋₆ alkylS—, C₁₋₆ alkyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkyl-C₁₋₄alkyl-, C₁₋₆alkenyl, C₁₋₆alkynyl, CF₃ CO—,C₁₋₆alkylCO—, C₃₋₆cycloalkylCO—, C₃₋₆cycloalkyl-C₁₋₄alkylCO—, phenyl,phenoxy, benzyloxy, benzoyl, phenyl-C₁₋₄alkyl-, or —NR⁵R⁶ where R⁵ ishydrogen or C₁₋₄ alkyl, and R⁶ is hydrogen, C₁₋₄alkyl, —CHO,—CO₂C₁₋₄alkyl or —COC₁₋₄alkyl;

[0007] R⁴ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkenyl, or C₁₋₆ alkynyl.

[0008] It has now been surprisingly found thattetrahydronaphthyridinyl-carboxamide compounds of formula (I) belowpossess anti-convulsant activity and are therefore believed to be usefulin the treatment and/or prevention of anxiety, mania, depression, panicdisorders and/or aggression, disorders associated with a subarachnoidhaemorrhage or neural shock, the effects associated with withdrawal fromsubstances of abuse such as cocaine, nicotine, alcohol andbenzodiazepines, disorders treatable and/or preventable withanti-convulsive agents, such as epilepsy including post-traumaticepilepsy, Parkinson's disease, psychosis, migraine, cerebral ischaemia.Alzheimer's disease and other degenerative diseases such as Huntingdon'schorea, schizophrenia, obsessive compulsive disorders (OCD),neurological deficits associated with AIDS, sleep disorders (includingcircadian rhythm disorders, insomnia & narcolepsy), tics (e.g. Giles dela Tourette's syndrome), traumatic brain injury, tinnitus, neuralgia,especially trigeminal neuralgia, neuropathic pain, dental pain, cancerpain, inappropriate neuronal activity resulting in neurodysthesias indiseases such as diabetes, multiple sclerosis (MS) and motor neuronedisease, ataxias, muscular rigidity (spasticity), temporomandibularjoint dysfunction, and amyotrophic lateral sclerosis (ALS).

[0009] Accordingly, the present invention provides a compound of formula(I):

[0010] where R¹ is hydrogen, C₁₋₆alkyl (optionally substituted byhydroxy or C₁₋₄alkoxy), phenyl-C₁₋₄alkyl-, C₁₋₆alkenyl, or C₁₋₆alkynyl;

[0011] R² is hydrogen or up to three substituents selected from halogen,NO₂, CN, N₃, CF₃O—. CF₃S—, CF₃SO₂—, CF₃CO—, C₁₋₆alkyl, C₁₋₆alkenyl,C₁₋₆alkynyl, C₁₋₆perfluoroalkyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkyl-C₄alkyl-, C₁₋₆alkylO—, C₁₋₆alkylCO—, C₃₋₆cycloalkylO—,C₃₋₆cycloalkylCO—, C₃₋₆cycloalkyl-C₁₋₄alkylO—,C₃₋₆cycloalkyl-C₁₋₄alkylCO—, phenyl, phenoxy, benzyloxy, benzoyl,phenyl-C₁₋₄alkyl-, C₁₋₆alkylS—, C₁₋₆alkylSO₂—) (C₁₋₄alkyl)₂NSO₂—,(C₁₋₄alkyl)NHSO₂—, (C₁₋₄alkyl)₂NCO—, (C₁₋₄alkyl)NHCO— or CONH;

[0012] or —NR⁵R⁶ where R) is hydrogen or C₁₋₄ alkyl, and

[0013] R⁶ is hydrogen, C₁₋₄alkyl, formyl, —COC₁₋₄alkyl or —COC₁₋₄alkyl;

[0014] or two R² groups together form a carbocyclic ring that issaturated or unsaturated, optionally interrupted by O or NH;

[0015] R³ groups and R⁴ groups are each independently hydrogen or C₁₋₆alkyl and/or the two R³ groups and/or the two R⁴ groups together form aC₃₋₆ spiroalkyl group, provided that at least one R³ or R⁴ group is nothydrogen; and

[0016] X is selected from hydrogen, halogen, cyano, alkyl and alkoxy.

[0017] The compounds of this invention aretetrahydronaphthyridinyl-carboxamides, especially(tetrahydronaphthyridin-3-yl)carboxamides. The carboxamide moiety istypically a benzamide, but when two R² groups form a carbocyclic ring,this is typically a 5-7 membered ring, and the carboxamide moiety may bea naphthalene carboxamide or an indane carboxamide, or when interruptedby O or NH may be a benzofuran carboxamide or an indole carboxamide.

[0018] In the formula (I), alkyl groups, including alkyl groups that arepart of other moieties, such as alkoxy or acyl, may be straight chain orbranched. Phenyl groups, including phenyl groups that are part of othermoieties, in R² may optionally be substituted with one or moreindependently selected halogen or C₁₋₆ alkyl. C₁₋₆ alkoxy or C₁₋₆alkylcarbonyl.

[0019] Suitable C₃₋₆ cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl. Suitable halo substituents include fluoro,chloro, iodo and bromo.

[0020] It should be appreciated that compounds of the present inventionpossess chiral centres and as such may exist in different enantiomericforms, the present invention extends to each enantiomeric form andmixtures thereof including diastereoisomers and racemates.

[0021] Preferably, the two R³ groups are the same, and the two R⁴ groupsare the same; typically either both R³ groups are gem-dialkyl orspiro-alkyl, preferably gem-dialkyl, and both R⁴ groups are hydrogen, orvice versa.

[0022] Accordingly one suitable group of compounds is of formula (IA)

[0023] A further suitable group is of formula (IB)

[0024] where R¹, R², R³, R⁴, X are as defined above.

[0025] A suitable group of compounds of formula (I) have

[0026] R¹ as hydrogen, methyl, ethyl, propyl, benzyl, hydroxyethyl,methoxyethyl,

[0027] R² as hydrogen or one or more of methyl, ethyl, n-butyl,iso-propyl, t-butyl, phenyl, methoxy, ethoxy, iso-propoxy,cyclopropylmethoxy, n-butoxy, phenoxy, benzyloxy, amino, acetylamino,nitro, azido, cyano, bromo, chloro, fluoro, iodo, acetyl, propionyl,pivaloyl, n-butyroyl, iso-butyroyl, benzoyl, iodobenzoyl,trifluoromethyl, perfluoroethyl, trifluoromethoxy, trifluoroacetyl,methanesulfonyl, n-propylsulfonyl, isopropylsulfonyl, dimethylsulfamoyl,

[0028] R³ one or both is hydrogen or methyl,

[0029] R⁴ one or both is hydrogen or methyl.

[0030] A preferred group of compounds of formula (I) have

[0031] R¹ as hydrogen, methyl,

[0032] R² as hydrogen or one or more of methyl, ethyl, i-propyl,t-butyl, methoxy, ethoxy, i-propoxy, bromo, chloro, cyano,trifluoromethyl,

[0033] R³ both methyl,

[0034] R⁴ both hydrogen.

[0035] Examples of compounds of formula (I) are:

[0036]N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)benzamide:

[0037]N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-cyano-4-iso-propylbenzamide:

[0038]N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-4-methoxy-3-trifluoromethylbenzamide:

[0039]N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-bromo-4-ethylbenzamide;

[0040]N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-bromo-4-ethoxybenzamide:

[0041]N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-chloro-4-iso-propyloxybenzamide:

[0042] N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-bromo-4-iso-propyloxybenzamide:

[0043]N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-acetyl-4-iso-propyloxybenzamide:

[0044]N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-4-ethoxy-3-trifluoromethylbenzamide;

[0045]N-(8,8-dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-methoxy-3-trifluoromethylbenzamide:

[0046]N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-bromo-4-methoxybenzamide;

[0047]N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-chloro-4-methoxybenzamide;

[0048]N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-cyano-4-methoxybenzamide;

[0049]N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-cyano-4-ethylbenzamide;

[0050]N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-bromo-4-methylbenzamide;

[0051]N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-pivaloylbenzamide;

[0052]N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-5-chloro-2-methoxy-4-iso-propyloxybenzamide;

[0053]N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-cyano-4-ethoxybenzamide;

[0054]N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-4-methoxy-3-trifluoroacetylbenzamide;

[0055]N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-yl)naphthalene-2-carboxamide;

[0056]N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-cyano-4-iso-propyloxybenzamide;

[0057]N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-acetyl-4-ethylbenzamide;

[0058]N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-yl)-2,3-dihydrobenzofuran-5-carboxamide;

[0059]N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-n-butyroyl-4-methoxybenzamide;

[0060]N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-4-methoxy-3-n-propionylbenzamide;

[0061]N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl-iso-butyroyl-4-methoxybenzamide;

[0062]N-(8,8-dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-ethoxy-3-trifluoromethylbenzamide;

[0063]N-(8,8-dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-acetyl-4-iso-propyloxybenzamide;

[0064]N-(8,8-dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-bromo-4-methoxybenzamide;

[0065]N-(8,8-dimethyl-5,6,7,8-tetrahydro[1,6naphthyridin-3-yl)-3-chloro-4-methoxybenzamide;

[0066]N-(8,8-dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-methoxy-3-pentafluoroethylbenzamide;

[0067]N-(8,8-dimethyl-5,6,7,8-tetrahydro(1,6]naphthyridin-3-yl)-4-iso-propoxy-3-trifluoromethylbenzamide:

[0068]N-(8,8-dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-ethyl-3-trifluoromethylbenzamide;

[0069]N-(8,8-dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-bromo-4-iso-propylbenzamide;

[0070]N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-chloro-4-ethoxybenzamide:

[0071]N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-fluoro-4-methoxybenzamide;

[0072]N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-4-methoxy-3-pentafluoroethylbenzamide;

[0073]N-(8,8-dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-yl)-3-fluoro-4-methoxybenzamide,

[0074]N-(8,8-dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-methoxy-3-propionylbenzamide,and;

[0075]N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-indole-2-carboxamide.

[0076] When synthesised, these compounds are often in salt form, such asthe hydrochloride or trifluoroacetate, and such salts also form part ofthis invention. Such salts may be used in preparing pharmaceuticallyacceptable salts. The compounds and their salts may be obtained assolvates, such as hydrates, and these also form part of this invention.

[0077] The above compounds and pharmaceutically acceptable saltsthereof, especially the hydrochloride, and pharmaceutically acceptablesolvates, especially hydrates, form a preferred aspect of the presentinvention.

[0078] The administration of such compounds to a mammal may be by way oforal, parenteral, sub-lingual, nasal, rectal, topical or transdermaladministration.

[0079] An amount effective to treat the disorders hereinbefore describeddepends on the usual factors such as the nature and severity of thedisorders being treated and the weight of the mammal. However, a unitdose will normally contain 1 to 1000 mg, suitably 1 to 500 mg, forexample an amount in the range of from 2 to 400 mg such as 2, 5, 10, 20,30, 40, 50, 100, 200, 300 and 400 mg of the active compound. Unit doseswill normally be administered once or more than once per day, forexample 1, 2, 3, 4, 5 or 6 times a day, more usually 1 to 4 times a day,such that the total daily dose is normally in the range, for a 70 kgadult of 1 to 1000 mg, for example 1 to 500 mg, that is in the range ofapproximately 0.01 to 15 mg/kg/day, more usually 0.1 to 6 mg/kg/day, forexample 1 to 6 mg/kg/day.

[0080] It is greatly preferred that the compound of formula (1) isadministered in the form of a unit-dose composition, such as a unit doseoral, including sub-lingual, rectal, topical or parenteral (especiallyintravenous) composition.

[0081] Such compositions are prepared by admixture and are suitablyadapted for oral or parenteral administration, and as such may be in theform of tablets, capsules, oral liquid preparations, powders, granules,lozenges, reconstitutable powders, injectable and infusable solutions orsuspensions or suppositories. Orally administrable compositions arepreferred, in particular shaped oral compositions, since they are moreconvenient for general use.

[0082] Tablets and capsules for oral administration are usuallypresented in a unit dose, and contain conventional excipients such asbinding agents, fillers, diluents, tabletting agents, lubricants,disinterants, colorants, flavourings, and wetting agents. The tabletsmay be coated according to well known methods in the art. Suitablefillers for use include cellulose, mannitol, lactose and other similaragents. Suitable disintegrants include starch, polyvinylpyrrolidone andstarch derivatives such as sodium starch glycollate. Suitable lubricantsinclude, for example, magnesium stearate. Suitable pharmaceuticallyacceptable wetting, agents include sodium lauryl sulphate.

[0083] These solid oral compositions may be prepared by conventionalmethods of blending, filling, tabletting or the like. Repeated blendingoperations may be used to distribute the active agent throughout thosecompositions employing large quantities of fillers. Such operations are,of course, conventional in the art.

[0084] Oral liquid preparations may be in the form of, for example,aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs,or may be presented as a dry product for reconstitution with water orother suitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, for example sorbitol,syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel or hydrogenated edible fats,emulsifying agents, for example lecithin, sorbitan monooleate, oracacia; non-aqueous vehicles (which may include edible oils), forexample, almond oil, fractionated coconut oil oily esters such as estersof glycerine, propylene glycol, or ethyl alcohol; preservatives, forexample methyl or propyl p-hydroxybenzoate or sorbic acid, and ifdesired conventional flavouring or colouring agents. Oral formulationsalso include conventional sustained release formulations, such astablets or granules having an enteric coating.

[0085] For parenteral administration, fluid unit dose forms are preparedcontaining the compound and a sterile vehicle. The compound, dependingon the vehicle and the concentration, can be either suspended ordissolved. Parenteral solutions are normally prepared by dissolving thecompound in a vehicle and filter sterilising before filling into asuitable vial or ampoule and sealing. Advantageously, adjuvants such asa local anaesthetic, preservatives and buffering agents are alsodissolved in the vehicle. To enhance the stability, the composition canbe frozen after filling into the vial and the water removed undervacuum.

[0086] Parenteral suspensions are prepared in substantially the samemanner except that the compound is suspended in the vehicle instead ofbeing dissolved and sterilised by exposure to ethylene oxide beforesuspending in the sterile vehicle. Advantageously, a surfactant orwetting agent is included in the composition to facilitate uniformdistribution of the compound of the invention.

[0087] As is common practice, the compositions will usually beaccompanied by written or printed directions for use in the medicaltreatment concerned.

[0088] Accordingly, the present invention further provides apharmaceutical composition for use in the treatment and/or prophylaxisof anxiety, mania, depression, panic disorders and/or aggression,disorders associated with a subarachnoid haemorrhage or neural shock,the effects associated with withdrawal from substances of abuse such ascocaine, nicotine, alcohol and benzodiazepines, disorders treatableand/or preventable with anti-convulsive agents, such as epilepsyincluding post-traumatic epilepsy, Parkinson's disease, psychosis,migraine, cerebral ischaemia, Alzheimer's disease and other degenerativediseases such as Huntingdon's chorea, schizophrenia, obsessivecompulsive disorders (OCD), neurological deficits associated with AIDS,sleep disorders (including circadian rhythm disorders, insomnia &narcolepsy), tics (e.g. Giles de la Tourette's syndrome), traumaticbrain injury, tinnitus, neuralgia, especially trigeminal neuralgia,neuropathic pain, dental pain, cancer pain, inappropriate neuronalactivity resulting in neurodysthesias in diseases such as diabetes,multiple sclerosis (MS) and motor neurone disease, ataxias, muscularrigidity (spasticity), temporomandibular joint dysfunction, andamyotrophic lateral sclerosis (ALS) which comprises a compound offormula (I), or a pharmaceutically acceptable salt or solvate thereof,and a pharmaceutically acceptable carrier.

[0089] The present invention also provides a method of treatment and/orprophylaxis of anxiety, mania, depression, panic disorders and/oraggression, disorders associated with a subarachnoid haemorrhage orneural shock, the effects associated with withdrawal from substances ofabuse such as cocaine, nicotine, alcohol and benzodiazepines, disorderstreatable and/or preventable with anti-convulsive agents, such asepilepsy including post-traumatic epilepsy, Parkinson's disease,psychosis, migraine, cerebral ischaemia, Alzheimer's disease and otherdegenerative diseases such as Huntingdon's chorea, schizophrenia,obsessive compulsive disorders (OCD), neurological deficits associatedwith AIDS, sleep disorders (including circadian rhythm disorders,insomnia & narcolepsy), tics (e.g. Giles de la Tourette's syndrome),traumatic brain injury, tinnitus, neuralgia, especially trigeminalneuralgia, neuropathic pain, dental pain, cancer pain, inappropriateneuronal activity resulting in neurodysthesias in diseases such asdiabetes, multiple sclerosis (MS) and motor neurone disease, ataxias,muscular rigidity (spasticity), temporomandibular joint dysfunction, andamyotrophic lateral sclerosis (ALS) comprising administering to thesufferer in need thereof an effective or prophylactic amount of acompound of formula (I), or a pharmaceutically acceptable salt orsolvate thereof.

[0090] In a further aspect the invention provides the use of a compoundof formula (I), or a pharmaceutically acceptable salt or solvatethereof, for the manufacture of a medicament for the treatment and/orprophylaxis of anxiety, mania, depression, panic disorders and/oraggression, disorders associated with a subarachnoid haemorrhage orneural shock, the effects associated with withdrawal from substances ofabuse such as cocaine, nicotine, alcohol and benzodiazepines, disorderstreatable and/or preventable with anti-convulsive agents, such asepilepsy including post-traumatic epilepsy. Parkinson's disease,psychosis, migraine, cerebral ischaemia, Alzheimer's disease and otherdegenerative diseases such as Huntingdon's chorea, schizophrenia,obsessive compulsive disorders (OCD), neurological deficits associatedwith AIDS, sleep disorders (including circadian rhythm disorders,insomnia & narcolepsy), tics (e.g. Giles de la Tourette's syndrome),traumatic brain injury, tinnitus, neuralgia, especially trigeminalneuralgia, neuropathic pain, dental pain, cancer pain, inappropriateneuronal activity resulting in neurodysthesias in diseases such asdiabetes, multiple sclerosis (MS) and motor neurone disease, ataxias,muscular rigidity (spasticity), temporomandibular joint dysfunction, andamyotrophic lateral sclerosis (ALS).

[0091] In a further aspect the invention provides the use of a compoundof formula (I), or a pharmaceutically acceptable salt or solvate,thereof as a therapeutic agent, in particular for the treatment and/orprophylaxis of anxiety, mania, depression, panic disorders and/oraggression disorders associated with a subarachnoid haemorrhage orneural shock, the effects associated with withdrawal from substances ofabuse such as cocaine, nicotine, alcohol and benzodiazepines, disorderstreatable and/or preventable with anti-convulsive agents, such asepilepsy including post-traumatic epilepsy, Parkinson's disease,psychosis, migraine, cerebral ischaemia, Alzheimer's disease and otherdegenerative diseases such as Huntingdon's chorea, schizophrenia,obsessive compulsive disorders (OCD), neurological deficits associatedwith AIDS, sleep disorders (including circadian rhythm disorders,insomnia & narcolepsy), tics (e.g. Giles de la Tourette's syndrome),traumatic brain injury, tinnitus, neuralgia, especially trigeminalneuralgia, neuropathic pain, dental pain, cancer pain, inappropriateneuronal activity resulting in neurodysthesias in diseases such asdiabetes, multiple sclerosis (MS) and motor neurone disease, ataxias,muscular rigidity (spasticity), temporomandibular joint dysfunction, andamyotrophic lateral sclerosis (ALS).

[0092] Another aspect of the invention is a process for the preparationof compounds of formula (I) as herein before described which comprisesreacting a compound of formula (II)

[0093] where R^(1A), R^(3A, and R) ^(4A) are R¹, R³, and R⁴ as definedfor formula (I) or a group or groups convertible to R¹, R³, and R⁴, andX is as defined for formula (I) with a compound of formula (III)

[0094] where Y is a leaving group such as Cl or OH, and R^(2A) groupsare independently R² as defined for formula (I) or a group or groupsconvertible to R², and where required converting an R^(1A), R^(2A),R^(3A), R^(4A) group to a R¹, R², R³, R⁴ group, converting one R¹, R²,R³, R⁴, X group to another R¹, R², R³, R⁴, X group, or separating anyenantiomers, or converting a salt product to the free base or anotherpharmaceutically acceptable salt, or converting a free base product to apharmaceutically acceptable salt.

[0095] Conventional conditions for condensation of amines withcarboxylic acids or active derivatives thereof, such as acid chlorides,may be used. For example the amides and acids may be reacted in thepresence of a mixture ofethyl(dimethylaminopropyl)-carbodiimide/hydroxybenzotriazole in asuitable solvent such as dimethyl formamide, and amines and acidchlorides may be reacted together in a suitable solvent such as ethylacetate or dichloromethane, optionally in the presence of a base such astriethylamine.

[0096] Conversions of an R^(1A), R^(2A), R^(3A), R^(4A) group to a R¹,R², R³, R⁴ group typically arise when a protecting group is neededduring the above coupling reaction or during the preparation of thereactants by the procedures described below. Interconversion of one R¹,R², R³, R⁴. X group to another typically arises when one compound offormula (I) is used as the immediate precursor of another compound offormula (I) or when it is easier to introduce a more complex or reactivesubstituent at the end of a synthetic sequence.

[0097] Reaction of a compound of formula (III) which is an acid chloride(Y=Cl) typically results in formation of the hydrochloride salt of thecompound of formula (I). Hydrochloride salts may also be obtained bypassing HCl gas into a solution of the free base product, or adding asolution of HCl in ether.

[0098] Compounds of formula (II) may be prepared from a compound offormula (IV),

[0099] by reaction with a dinitro-1-methylpyrid-2-one compound offormula

[0100] in a solution of ammonia in a suitable solvent such as methanol,to obtain a compound of formula (VI) using a procedure similar to thatof S. Takada et al. J. Med. Chem, 1996, 39, 2844.

[0101] Compounds of formula (VI) may be converted to compounds offormula (II) by hydrogenation or reduction of the nitro group. Forexample, a compound of formula (VI) may be hydrogenated by treatmentwith hydrogen in a suitable solvent such as methanol in the presence ofa palladium/carbon catalyst. Alternatively, a compound of formula (VI)may be reduced with stannous chloride in concentrated hydrochloric acidin a suitable solvent such as ethanol.

[0102] Compounds of formula (IV) may be prepared using the procedures ofKatyalyan et al., Bull. Acad. Sci. USSR (Engl) 1968. 2436.

[0103] Compounds of formula (V) may be prepared using the procedure ofE. Matsumura. M. Ariga and Y. Tohda. Bull. Chem. Soc. Japan, 52 (8),2413-2419,(1979).

[0104] Compounds of formula (III) may be prepared by furthersubstitution of commercially available benzoic acid derivatives usingconventional procedures, or by oxidation of corresponding substitutedbenzyl alcohols. Alternatively benzoic acids can be prepared fromcorrepondingly substituted phenols, for example by formation of theacetate, coversion to an acetophenone and then to the desired acid.

[0105] Where the above described intermediates are novel compounds, theyalso form part of this invention.

[0106] The preparation of compounds of formula (II) is illustrated bythe following Descriptions; the preparation of compounds of formula(III) is illustrated by the following Preparations and Procedures: thepreparation of compounds of this invention is illustrated by thefollowing Examples. The utility of compounds of this invention is shownby the Pharmacological Data that follow the Examples.

[0107] Description 1

[0108] 1,3,3-Trimethylpiperidio-4-one

[0109] The title compound was prepared according to the procedure ofKatyalyan et al. Bull. Acad. Sci. USSR (Engl) 1968, 2436. b.p 70° C. at16 mm Hg; ^(m)/_(z) (API⁺): 142.1 (MH+)

[0110] Description 2

[0111] 3-Nitro-3,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridine

[0112] 3,5-Dinitro-1-methylpyridin-2-one [prepared by the method of E.Matsumura. M. Ariga and Y. Tohda. Bull. Chem. Soc. Japan. 1979. 52.2413-2419] (2g: 10 mmol) was suspended in MeOH (50 ml) and treated with0.88 aq. ammonia (10 ml; 157 mmol), 1,3,3-Trimethylpiperidin-4-one (1.7g; 12 mmol) was added and the mixture heated at 70° C. for 5 h. Themixture was cooled to room temperature then evaporated to dryness invacuo. The residue was digested with dichloromethane (2×50 ml) and thehot solution decanted from the red gum. The extracts were combined,evaporated to dryness in vacuo and the residue purified bychromatography on SiO₂, with 50% ethyl acetate:60-80° C. petroleum togive the title compound as a yellow oil, which solidified on standing(1.05 g: 48%).

[0113]¹H NMR (250 MHz: CDCl₃) δ: 1.38 (6H, s), 2.47 (3H, s), 2.55 (2H,s), 3.64 (2H, s), 8.09 (1H, d, J=3 Hz), 9.25 (1H, d, J=3 Hz); ^(m)/_(z)(APE⁺): 222.1 (MH+)

[0114] Description 3

[0115] 3-Amino-5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridine

[0116] The product from Description 2 (930 mg; 4.20 mmol) was dissolvedin MeOH (30 ml) and the mixture treated with 10% palladium on carbon(150 mg) then hydrogenated at STP until hydrogen uptake ceased. Catalystwas removed by filtration through Celite and the filtrate and washingscombined and evaporated to dryness in vacuo. The residue was trituratedunder diethyl ether containing a little dichloromethane and the titlecompound collected by filtration washed with diethyl ether and dried invacuo (795 mg: 84%).

[0117]¹H NMR (250 MHz: CD₃OD) δ_(H): 1.73-1.99 (2H, m), 2.34-2.55 (5H,m), 2.63 (1H, d, J=17 Hz), 3.29 and 3.36 (1H, dd. J=17.5 Hz), 3.66-3.71(1H, m), 3.99(1H, d, J=6 Hz), 6.95 (1H, d, J=3 Hz), 7.95 (1H, d, J=3Hz): ^(m)/_(L) (API⁺): 190.16 (MH+).

[0118] Preparation 1

[0119] 3-Bromobenzyl TBMS ether

[0120] To a solution of 3-bromobenzyl alcohol (5.00 g. 0.027 mole) indichloromethane (30 ml). Et₃N (4.2 ml, 0.03 mole) was added a 1 Msolution tert-butyldimethylsilyl chloride in dichloromethane (28.0 ml)dropwise. The mixture Was allowed to stir at room temperature overnight,then water (30 ml) was added. The organic layer was washed with brine,dried (Na₂SO₄) and evaporated to give a red oil which was purified byflash chromatography on silica gel using 20% ether in hexane to give acolouorless oil (8.0 g).

[0121] Preparation 2

[0122] 3-Pivaloylbenzylalcohol TBDMS Ether

[0123] n-Butyllithium (2.80 ml, 7.00 mmol. 2.5M in hexane) was slowlyadded to a solution of Preparation 1 TBDMS ether (1.80 g. 6.0 mmol) indry THF (10 ml) over 5 min at −78° C. The reaction mixture wasmaintained under argon at −78° C. for 1 h, and N,O-dimethyl-hydroxypivaloyl amide (0.86 g. 6.60 mmol) in THF (2 ml) was added dropwise withstirring at −78° C. The resulting mixture was allowed to stir at −78° C.for 2.5 h, quenched with NH₄Cl solution and allowed to warm to roomtemperature. The mixture was extracted with ether (2×50 ml), thecombined organics were dried (Na₂SO₄) and concentrated in vacuo to givethe title compound as a colourless oil (1.75 g ^(m)/_(z) (API+) 307(MH⁺; 8%).

[0124] Preparation 3

[0125] 3-Pivaloylbenzylalcohol

[0126] The ether of Preparation 2 (1.470, 4.80 mmol) was dissolved inmethanol (25 ml): conc. HCl (20 drops) was added and the whole allowedto stir at room temperature for 4 h. Saturated NaHCO₃ solution was addedand the mixture extracted with ether (2×50 ml). The organic layer wasdried over sodium sulfate and evaporation in vacuo save title compoundas a colourless oil (0.80 g).

[0127]^(m)/_(z) (API+): 193 (MH⁺: 17%).

[0128] Preparation 4

[0129] 3-Pivaloylbenzoic Acid

[0130] 3-Pivaloylbenzyl alcohol (0.80g, 4.16 mmol) was dissolved indioxane (20 ml). A solution of KOH (0.35 g. 6.30 mmol) in water (5 ml)was added followed by KMnO₄ (1.45 g, 9.17 mmol). The mixture was stirredat room temperature over the weekend. The solution was filtered throughCelite and extracted with ether. The aqueous phase was acidified withdil. HCl and extracted with ether (3×50 ml). The organic layer was driedover magnesium sulphate and concentrated in vacuo to afford the titlecompound as a white solid (0.80 g).

[0131]¹H NMR (250 MHz, CDCl₃)δ: 1.38 (9H, s), 7.55 (1H, t), 7.92 (1H, d,J=6.5 Hz), 8.20 (1H, d, J=6.5 Hz), 8.44 (1H, s).

[0132] Preparation 5

[0133] 3-Trifluoroacetylbenzoic Acid

[0134] The title compound was prepared from diethyl trifluoroacetamideand 3-bromobenzyl TBDMS ether using a method similar to that describedin Preparations 1, 2, 3 and 4.

[0135]^(m)/_(z) (API−): 217 (M−H⁺: 20%).

[0136] Preparation 6

[0137] Methyl 3-Chloro-4-iso-propoxybenzoate

[0138] Methyl 3-chloro-4-hydroxybenzoate (5 g, 26.8 mmol) in DMF (45 ml)was treated with potassium carbonate (7.41 g. 53.6 mmol), 2-iodopropane(3.85 ml. 40.2 mmol) and then stirred at 25° C. for 18 h. Work-up withethyl acetate (save the title compound (6.1 g).

[0139] Preparation 7

[0140] 3-Chloro-4-iso-propoxybenzoic acid

[0141] Methyl 3-chloro-4-iso-propoxybenzoate (5.5 g. 24.1 mmol) washydrolysed using 1M NaOH (36 ml) in methanol (80 ml). Extraction andwork-up with ethyl acetate gave the title compound (4.3 g).

[0142]¹H NMR (DMSO-D₆) δ: 1.33 (6H, d), 4.79 (1H, m), 7.24 (1H, d), 7.87(2H, m).

[0143] Preparation 8

[0144] 3-Bromo-4-ethoxybenzoic Acid

[0145] The title compound was prepared from 4-ethylbenzoic acid in amanner similar to that of Procedure 1.

[0146]¹H NMR (DMSO-D₆) δ: 1.45 (3H, t, J=7 Hz), 4.26(2H, q, J=7 Hz) 7.26(1H, d, J=9 Hz), 7.98(1H, d, J=2.9 Hz), 8.12(1H, d, J=2 Hz)

[0147] Preparation 9

[0148] 3-Bromo-4-ethylbenzoic Acid

[0149] The title compound was prepared from 4-ethylbenzoic acid in amanner similar to that of Procedure 1.

[0150]¹H NMR (DMSO-D₆) δ: 1.20 (3H, t, J=7 Hz), 2.78 (2H, q, J=7 Hz),7.50 (1H, d, J=8 Hz), 7.90(1H, dd, J=2.8 Hz), 8.07 (1H, d, J=8 Hz

[0151] Preparation 10

[0152] 3-Cyano-4-iso-propylbenzoic Acid

[0153] The title compound was prepared from 4-iso-propylbenzoic acidusing a manner similar to that described in Procedures 1 and 5.

[0154]¹H NMR (DMSO-D₆) δ: 1.07 (6H, d, J=7 Hz), 0.13 (1H, m,overlapped), 7.48 (1H, d, J=7 Hz), 7.96(1H, dd. J=2.8 Hz)), 8.00 (1H, d,J=2 Hz).

[0155] Preparation 11

[0156] 4-Methoxy-3-trifluoromethylbenzoic Acid

[0157] The title compound was prepared from 3-bromo-4-methoxybenzoicacid and potassium trifluoroacetate in a manner similar to that ofProcedures 3 and 4.

[0158]¹H NMR (DMSO-D₆) δ: 3.78 (3H, s), 7.18 (1H, d, J=9 Hz), 7.90(1H,d, J=2 Hz), 8.00 (1H, dd. J=2.9 Hz), 12.70-13.10 (1H, br, exchangeable)

[0159] Preparation 12

[0160] 4-Methoxy-3-trifluoromethylbenzoyl Chloride

[0161] The title compound was prepared from4-methoxy-3-trifluoromethylbenzoic acid with oxalyl chloride and DMF inchloroform at room temperature [D. Levin. Chem. Br. 1977. 20] followedby evaporation in vacuo

[0162] Preparation 13

[0163] Methyl 3-Bromo-4-iso-propoxybenzoate

[0164] Methyl 3-bromo-4-hydroxybenzoate (2.5 g. 10.8 mmol) in DMF (35ml) was treated with potassium carbonate (3.0 g, 21.6 mmol),2-iodopropane (2.76, 21.6 mmol) and then stirred at 25° C. for 48 h.Work-up with ethyl acetate gave the title compound (3.0 g).

[0165]¹H NMR (250 MHz, CDCl₃) δ: 1.41 (6H, d, J=7 Hz), 3.89 (3H, s),4.66 (1H, m), 6.90 (1H, d, J=8 Hz), 7.93 (1H, dd. J=8.2 Hz), 8.22 (1H,d, J=2 Hz)

[0166] Preparation 14

[0167] Methyl 3-Cyano-4-iso-propoxybenzoate

[0168] Methyl 3-bromo-4-iso-propoxybenzoate (2.0 g. 7.3 mmol) andcopper(I)cyanide in N-methyl pyrrolidone (50 ml) was heated undervigorous reflux for 4 h. Work-up with ethyl acetate gave the titlecompound (1.0 g).

[0169]¹H NMR (250 MHz. CDCl₃) δ: 1.56 (6H, d, J=7 Hz), 4.05 (3H, s),4.88 (1H, m), 7.13 (1H, d, J=8 Hz), 8.31 (1H, dd. J=8.2 Hz), 8.31 (1H,d. J=2 Hz)

[0170] Preparation 15

[0171] Methyl 3,5 Dichloro-4-ethoxybenzoate

[0172] The title compound was prepared in 69% yield from methyl3,5-dichloro-4-hydroxybenzoic acid and iodoethane in a manner similar tothat of Preparation 6.

[0173]¹H NMR (250 MHz. CDCl₃) δ: 1.47 (3H, t, J=7 Hz), 3.91 (3H, s),4.16 (2H, q, J=7 Hz). 7.96 (2H, s).

[0174] Preparation 16

[0175] 3-Methanesulfonyl-4-iso-propylbenzoic Acid

[0176] 3-Chlorosulfonyl-4-iso-propylbenzoic acid (2.62 g. 10 mmol) [madefrom 4-iso-propyl benzoic acid in a manner similar to that described inProcedures 7 and 8] was added slowly to a slurry of NaHCO₃ (2.52 g. 30mmol) and Na₂SO₃ (1.26 g 10 mmol) in water (9 ml) at 75° C. The mixturewas stirred for 1 h and then treated with bromoacetic acid (2.08 g. 15mmol) and NaOH (0.60 g, 15 mmol). The temperature was raised to 105° C.and the mixture heated at reflux for 24 h. The mixture was cooled,acidified to pH 1 and the resultant precipitate collected, washed anddried to give the title compound (1.43 g. 59%).

[0177]¹H NMR (250 MHz. acetone-D₆) δ: 1.24 (6H, d, J=7 Hz), 3.13 (3H,s), 3.88 (1H, m), 7.72 (1H, d, J=7 Hz), 8.15(1H, dd, J=7 Hz), 8.52(1H,d, J=7 Hz).

[0178] Preparation 17

[0179] 3-Chloro-4-ethoxybenzoic Acid

[0180]¹H NMR (DMSO-D₆) δ: 1.39 (3H, t. J=7 Hz), 4.20 (2H, q, J=7 Hz),7.22 (1H, d, J=7 Hz), 7.87 (2H, m).

[0181] Preparation 18

[0182] 3-Bromo-4-iso-propoxybenzoic Acid

[0183] The title compound was prepared using a method similar to that ofPreparation 7.

[0184]¹H NMR (DMSO-D₆) δ: 1.29 (6H, d, J=7 Hz), 4.77 (1H, sep. J=7 Hz),7.20 (1H, d, J=8 Hz), 7.87(1H, dd, J=8.2 Hz), 8.02(1H, d, J=2 Hz),12.92(1H, brs).

[0185] Procedure 1

[0186] 5-Bromo-2,4-dimethoxybenzoic Acid

[0187] To a solution of 2.4-dimethoxybenzoic acid (4.0 g. 0.022 mol) inchloroform (60 ml) was added bromine (1.13 ml. 0.022 mol) in chloroform(20 ml) dropwise. After stirring overnight at room temperature theprecipitate was filtered off and dried to afford the title compound as awhite solid (2.87 g).

[0188] Procedure 2

[0189] 5-Bromo-4-iso-propyl-2-methoxybenzoic Acid

[0190] To a solution of 2-methoxy-4-iso-propyl benzoic acid (7.0 g. 36.0mmol) in chloroform (100 ml) was added bromine (1.86 ml) in chloroform(20 ml) dropwise. The reaction was stirred at room temperatureovernight. Evaporation in vacuo afforded an oil (9.27 g). ^(m)/_(z)(Cl): 275, 273 (MH⁻: 70%).

[0191] Procedure 3

[0192] Methyl-5-bromo-4-iso-propyl-2-methoxy Benzoate

[0193] 5-Bromo4-iso-propyl-2-methoxybenzoic acid (9.268 g 34.0 mmol) wasdissolved in ethanol (250 ml) and conc. H₂SO₄ (2 ml) added. The mixturewas refluxed for 5 h and concentrated in vacuo. Residual material wastaken up into ethyl acetate and water, and the organic layer, dried(MgSO₄) Concentration in vacuo afforded an oil, which was purified byBiotage Column Chromatography on silica gel using 10% ether in hexane togive an oil (5.5 g).

[0194] Procedure 4

[0195] 2,4-Dimethoxy-5-trifluoromethylbenzoic Acid

[0196] 2.4-Dimethoxy-5-bromobenzoic acid methyl ester (1.5 g; 5.4 mmol)in DMF (25 ml) and toluene (8 ml) under argon was treated with potassiumtrifluoroacetate (1.53 g, 10.1 mmol) and copper (I) iodide (2.1 g. 10.9mmol). The mixture was heated to 170° C. with removal of water(Dean/Stark), and then at 155° C. overnight. The mixture was allowed tocool, poured into ether and water and filtered through Kieselguhr. Theorganic layer was dried (Na₂SO₄) and concentrated in vacuo to give abrown solid. Chromatography on Kieselgel 60 with 1:1 ether/petrol gave asolid (1.03 g) which was hydrolysed in 1:1 methanolic: aqueous NaOH (50ml) at 50° C. Work-up gave the title compound as a white solid (1 g).

[0197] Procedure 5a

[0198] Methyl 2-methoxy-5-cyano-4-iso-propylbenzoate

[0199] Copper (I) cyanide (550 mg, 6 mmol) was added to a solution ofmethyl 2-methoxy-5-bromo-4-iso-propylbenzoate (861 mg) inN-methyl-2-pyrolidinone (30 ml). The mixture was stirred under argon andboiled under reflux for 4 h. The mixture was cooled, poured into excessice/water and ethyl acetate and filtered. The organic phase wasseparated, washed with water, brine and dried(MgSO₄). Evaporation gave acrude brown solid which was purified by chromatography on silica geleluting with ethyl acetate/n-hexane (1:4). The product was obtained as awhite solid (523 mg).

[0200]¹H NMR (250 MHz. CDCl₃) δ: 1.33 (6H, d. J=7 Hz), 3.38 (1H, sep.J=7 Hz), 3.89 (3H, s). 3.98 (3H, s), 6.91 (1H, s), 8.08 (1H, s):^(m)/_(z) (API⁺): 234 (MH⁺. 30%).

[0201] Procedure 5b

[0202] 2-Methoxy-5-cyano-4-iso-propylbenzoic Acid

[0203] 2N NaOH (1.25 ml) was added to a solution of the methyl ester P5a(490 mg) in methanol (10 ml). The solution was stirred overnight at roomtemperature. The solution was then diluted with water, concentrated invacuo and washed with ethyl acetate. The aqueous phase was thenacidified with 2N HCl and extracted with ethyl acetate. The extract waswashed with brine, dried (MgSO₄) and evaporated to dryness giving theproduct as a white solid (418 mg).

[0204]¹H NMR (250 MHz. CDCl₃) δ: 1.35 (6H, d. J=7 Hz), 3.43 (1H, sep.J=7 Hz), 4.14 (3H, s), 7.00 (1H, s), 8.41 (1H, s); ^(m)/_(z) (API⁺): 220(MH⁺, 100%).

[0205] Procedure 6a

[0206] Ethyl 2-ethoxy-4-iso-propyl-5-cyanobenzoate

[0207] Ethyl 2-ethoxy-4-iso-propyl-5-bromobenzoate (1.2 g, 3.8 mmol) wastreated with copper (I) cyanide (682 mg, 7.6 mmol) inN-methyl-2-pyrrolidinone (40 ml) as described in Procedure 5 to give thetitle compound as an oil (400 mg).

[0208]¹H NMR (230 MHz. CDCl₃) δ: 1.12 (6H, d, J=7 Hz), 1.30 (3H, t, J=7Hz), 1.84 (3H, t, J=7 Hz), 3.17 (1H, sep. J=7 Hz), 3.99 (2H, q, J=9 Hz),4.16 (2H, q, J=7 Hz), 6.69 (1H, s). 7.86 (1H, s): ^(m)/_(z) (API⁺): 262(MH⁺. 100%).

[0209] Procedure 6b

[0210] 2-Ethoxy-4-iso-propyl-5-cyanobenzoic Acid

[0211] The ester P6a (370 mg. 1.41 mmol) was dissolved in methanol (5ml) and over a 24 h period 1N NaOH (2.1 ml. 2.1 mmol) was added. Thesolution was concentrated under vacuum, diluted with water and washedwith ethyl acetate. The aqueous phase was acidified with 2N HCl andextracted with ethyl acetate. The extract was washed with brine, dried(Mg SO₄) and evaporated to give the title acid (306 mg).

[0212]¹H NMR (250 MHz CDCl₃) δ: 1.39 (3H, d, J=7 Hz), 1.66 (3H, t, J=7Hz), 3.47 (1H, sep, J=7 Hz), 4.46 (1H, q, J=7 Hz), 7.03 (1H, s), 8.47(1H, s): ^(m)/_(z) (API⁺): 234 (MH⁺. 100%).

[0213] Procedure 7

[0214] 4-Ethoxy-2-methoxy-5-methylsulfonylbenzoic Acid

[0215] 4-Ethoxy-2-methox-5-chlorosulfonyl benzoic acid in a 49% yield,was prepared in 49% yield using the procedure of M. W. Harrold et al. J.Med. Chem. 1989. 32 874. This was used according to the method of R. W.Brown. J. Org. Chem. 1991. 56. 4974, to the title compound in 19% yield.

[0216]¹H NMR (DMSO-D₆) δ: 1.30 (3H, t), 3.10 (3H, s), 3.83 (3H, s), 4.24(2H q), 6.73 (1H. s), 8.07 (1H, s).

[0217] Procedure 8

[0218] 4-iso-Propyl-2-methoxy-3-methylsulfonylbenzoic acid

[0219] This was prepared in a similar manner to the procedure of C.Hansch. B. Schmidhalter. F. Reiter. W. Saltonstall J. Org. Chem., 1956.21, 265 to afford the intermediate5-chlorosulfonyl-4-isopropyl-2-methoxybenzoic acid which was convertedinto the title compound using the method of Procedure 7.

[0220]¹H NMR (DMSO-D₆) δ: 1.30 (6H, d), 3.21 (3H, s), 3.80 (1H, m), 3.94(3H, s), 7.26 (1H, s), 8.19 (1H, s).

EXAMPLE 1

[0221] N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)benzamide Hydrochloride

[0222] 3-Amino-5,6,7,8-tetrahydro-6,8,8-trimethyl [1,6]naphthyridine (96mg, 0.50 mmol) was dissolved in dry THF (5 ml) and the solution treatedwith benzoyl chloride (70.3 mg; 0.50 mmol). The mixture was stirred atambient temperature for 2 h then the precipitate collected byfiltration, washed with THF, diethyl ether and dried in vacuo (132 mg;80%).

[0223]¹H NMR (250 MHz. (CD₃)₂SO) δ: 1.42 and 1.54 (2×3H, s), 3.02 (3H,brs), 3.65 (2H, brm), 4.40-4.70 (2H, brm), 7.60-7.71 (3H, m), 8.00-8.10(2H, m), 8.18 (1H, brs), 8.91 (1H, brs), 10.60-10.90 (2H, brm,exchangeable); ^(m)/_(z) (API⁺): 296.1 (MH+).

EXAMPLE 2

[0224]N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-cyano-4-iso-propylbenzamideHydrochloride

[0225] Prepared in a manner similar to that of Example 1, from3-cyano-4-iso-propylbenzoic acid as a white powder (171 mg. 86%).

[0226]¹H NMR (250 MHz, (CD₃)₂SO) δ: 1.30 (6H, d, J=7 Hz), 1.33 and 1.46(2×3H, s), 2.94 (3H, d, J=4 Hz), 3.20-3.70 (3H, brm), 4.30-4.60 (2H, m),7.73 (1H, d, J=8 Hz), 8.09 (1H, d, J=2 Hz), 8.24(1H, dd. J=10.2 Hz),8.40(1H, d, J=2 Hz), 8.83 (1H, d, J=2 Hz); ^(m)/_(z) (API⁺): 363.2(MH+).

EXAMPLE 3

[0227]N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-4-methoxy-3-trifluoromethylbenzamideHydrochloride

[0228] Prepared in a manner similar to that of Example 1 from4-methoxy-3-trifluoromethyl-benzoic acid. The product was purified bychromatography on SiO₂, eluting with 0.88 aq.ammonia/methanol/dichloromethane (0.5:4.5:95), and converted into thehydrochloride salt by addition of 1M hydrogen chloride in diethyl ether(1 equivalent). The title compound was collected by filtration (98 mg.46%).

[0229]¹H NMR (250 MHz: (CD₃)₂SO) δ: 1.6 and 1.48 (2×3H, s), 2.96 (3H, d,J=3 Hz), 3.40 and 3.70 (2×1H, brm), 3.99 (3H, s), 4.30-4.60 (2H, br),7.46 (1H, d, J=9 Hz), 8.10 (1H, d. J=2 Hz), 8.28 (1H brs), 8.34 (1H, brdd), 8.85 (1H, d, J=2 Hz), 10.60-10.80 (2H, br, exchangeable): ^(m)/_(z)(API⁺): 394.2 (MH+).

EXAMPLE 4

[0230]N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-bromo-4-ethylbenzamideHydrochloride

[0231] Prepared in a similar manner to that of Example 3 from3-bromo-4-ethylbenzoic acid and isolated as an off-white powder (104 mg;46%).

[0232]¹H NMR (250 MHz; (CD₃)₂SO) δ: 1.25 (3H, t, J=7 Hz), 1.40 and 1.54(2×3H, s), 2.83 (2H, q, J=7 Hz) 3.00 (3H, d, J=4 Hz), 3.30-3.80 (2H,brm) 4.30-4.70 (2H, m), 7.59 (1H, d, J=8 Hz), 8.02 (1H, d, J=8 Hz), 8.16(1H, d, J=2 Hz), 8.26 (1H, d, J=1 Hz), 8.90 (1H, d, J=2 Hz): ^(m)/_(z)(API+): 402.1, 404.1 (MH+).

EXAMPLE 5

[0233] N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6naphthyridin-3-yl)-3-bromo-4-ethoxybenzamide Hydrochloride

[0234] Prepared in a similar manner to that of Example 3 from3-bromo-4-ethoxybenzoic acid and isolated as an off-white powder (100mg: 44%).

[0235]¹H NMR (250 MHz: (CD₃)₂SO) δ: 1.42 and 1.55 (2×3H, s), 1.46 (3H,t, J=,7 Hz), 3.01 (3H, brd), 3.30-3.80 (2H, m), 4.29 (2H, q, J=2 Hz),4.30-4.70 (2H, brm), 7.33 (1H, d, J=9 Hz), 8.10 (1H, dd. J=9.2 Hz), 8.16(1H, d, J=2 Hz), 8.33 (1H, d, J=2 Hz), 8.91 (1H, d, J=2 Hz), 10.64 (1H,s, exchangeable), 10.86 (1H, br, exchangeable). ^(m)/_(z) (API⁺): 418.1,420.1 (MH+).

EXAMPLE 6

[0236]N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-chloro-4-iso-propyloxybenzamideHydrochloride

[0237] Prepared in a manner similar to that of Example 3 from3-chloro-4-iso-propyloxybenzoic acid and isolated as an off-white powder(67 mg; 32%).

[0238]¹H NMR (250 MHz (CD₃)₂SO) δ: 1.17 (6H, d, J=6 Hz), 1.22 and 1.50(2×3H, s), 2.78 (3H, brs), 3.40 (2H, brs), 4.20-4.60 (2H, brm),4.63-4.73 (1H, m), 7.18 (1H, d. J=9 Hz), 7.85(1H, dd. J=9.2 Hz), 7.97(1H, d, J=2 Hz), 8.04(1H, d, J=Hz), 8.75 (1H, d. J=2 Hz); ^(m)/_(z)(API⁺): 388.2, 390.2 (MH+).

EXAMPLE 7

[0239]N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-bromo-4-iso-propyloxybenzamideHydrochloride

[0240] Prepared in a manner similar to that of Example 3 from3-bromo-4-iso-propyloxybenzoic acid and isolated as an off-white powder(224 mg: 82%).

[0241]¹H NMR (250 MHz: (CD₃)₂SO) δ:1.24 (6H, d. J=6 Hz), 1.26 and 1.35(2×3H, s), 2.89 (3H, brd), 3.30(2H, brm), 4.20-4.50 (2H, brm), 4.74(1H,m), 7.20 (1H, d, J=9 Hz), 7.90 (1H, dd. J=9.2 Hz), 7.92 (1H, d, J=2 Hz),8.15 (1H, d, J=2 Hz), 8.72 (1H, d, J=2 Hz): ^(m)/_(z) (API⁺): 434, 432(MH+; 80%).

EXAMPLE 8

[0242]N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphtliyridin-3-yl)-3-acetyl-4-iso-propyloxybenzamideHydrochloride

[0243] Prepared as described in Example 3 from3-acetyl-4-iso-propyloxybenzoic acid (222 mg: 1.0 mmol), except that thereaction was performed in dichlioromethane and in the presence oftriethylamine (101 mg: 1.0 mmol: 0.14 ml). The title compound wasisolated as a white powder (247 mg; 57%).

[0244]¹H NMR [free base] (250 MHz: CD₃OD) δ: 1.22 (6H, s), 1.32 (6H, d,J=6 Hz), 2.31 (3H, s), 244 (2H, s), 2.50(3H, s), 3.45(21H, s), 4.77(1H,m), 7.12 (1H, d, J=9 Hz), 7.79 (1H, d, J=2 Hz), 7.95 and 7.99 (1H, dd,J=9, 2 Hz). S. 16 (1H, d, J=2 Hz), 8.56 (1H, d. J=2 Hz); ^(m)/_(z)(API)⁺: 396.2 (MH+; 80%).

EXAMPLE 9

[0245]N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-4-ethoxy-3-trifluoromeethylbenzamideDihydrochloride

[0246] Prepared as described in Example 8 from4-ethoxy-3-trifluoromethylbenzoic acid (237 mg; 1.0 mmol) and isolatedas a white powder (416 mg: 87%).

[0247]¹H NMR [free base] (250 MHz: CD₃OD) δ: 1.23 (6H, s), 1.34 (3H, t.J=7 Hz), 2.32 (3H, s), 2.45 (2H, s), 3.46(2H, s), 4.13 (2H, q, J=7 Hz),7.16(1H, d, J=9 Hz), 7.80 (1H, d, J=2 Hz), 8.09 (2H, m), 8.57 (1H, d.J=2 Hz). ^(m)/_(z) (API)⁺: 408.2 (MH+: 80%).

EXAMPLE 10

[0248] N-(8,8-Dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-methoxy-3-trifluoromethylbenzamideHydrochloride

[0249]N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-4-methoxy-3-trifluoromethylbenzamide(172 mg; 0.44 mmol) was suspended in 1.2-dichloromethane (30 ml) and themixture treated with 1-chloroethyl chloroformate (62.5 mg: 47 ml; 0.44mmol). The mixture was heated at reflux and more chloroformate addeduntil little or no starting material remained. At this point, thevolatiles were removed under reduced pressure and the residue dissolvedin methanol (30 ml) and heated at reflux for 15 min. The volatiles wereremoved under reduced pressure and the residue treated with a mixture of0.88 aqueous ammonia/methanol/dichloromethane (0.5: 4.5:95) and theresulting, beige solid was collected by filtration. The free base (123mg; 0.32 mmol) was dissolved in methanol (min. vol) and treated with IMhydrogen chloride in diethyl ether (0.32 ml: 0.32 mmol) and the mixturediluted with diethyl ether to turbidity and refrigerated. The titlecompound was obtained as white powder (130 mg: 71%).

[0250]¹H NMR [free base] (250 MHz: CD₃OD) δ: 1.37 (6H, s), 3.35 (2H, s),4.5 (2H, s), 7.25 (1H, d, J=9 Hz), 3.07 (1H, d, J=2 Hz), 8.15-8.18 (2H,m), 8.70 (1H, d, J=2 Hz): m/z (API)⁺: 373.1 (MH+; 100%).

[0251] The following examples were prepared using methods describedabove:

EXAMPLE 11

[0252]N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-bromo-4-methoxybenzamideHydrochloride

[0253]¹H NMR [free base] (250 MHz: CD₃OD) δ: 1.04 (6H, s), 2.13 (3H, s),2.26 (2H, s), 3.27 (2H, s), 3.65 (3H, s), 6.84 (1H, d. J=9 Hz), 7.59(1H, d, J=2 Hz), 7.66(1H, dd. J=9,2 Hz), 7.88 (1H, d, J=2 Hz), 8.37 (1H,d, J=2 Hz): m/z (API)⁺: 425.7, 428 (M+Na+).

EXAMPLE 12

[0254]N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-chloro-4-methoxybenzamideHydrochloride

[0255]¹H NMR [free base] (250 MHz: CD₃OD) δ1.41 (6H, s), 2.50 (3H, s),2.64 (2H, s), 3.56 (2H, s), 4.03 (3H, s), 7.26(1H, d, J=9 Hz), 7.97-8.09(3H, m), 8.73 (1H, d, J=2 Hz); m/z (API)⁺: 382.1, 384.2 (M+Na)⁺.

EXAMPLE 13

[0256]N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-cyano-4-methoxybenzamideHydrochloride

[0257]¹H NMR [free base] (250 MHz: CD₃OD) δ: 1.33 (6H, s), 2.43 (3H, s),2.56 (2H, s), 3.58 (2H, s), 4.03 (3H, s), 7.31 (1H, d, J=9 Hz), 7.90(1H,d, J=2 Hz), 8.23 (2H, m), 8.66 (1H, d, J=2 Hz): m/z (API)⁺: 351.1 (MH⁺.80%), 373.2 (M+Na)⁺.

EXAMPLE 14

[0258]N-(5,6,7,8-Tetrahydo-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-cyano-4-ethylbenzamideHydrochloride

[0259]¹H NMR [free base] (250 MHz. CD₃OD) δ: 1.10 (9H, m), 2.20 (3H, s),2.34 (2H, s), 2,71 (2H, q, J=8 Hz), 3.36 (2H, s), 7.37 (1H, d, J=8Hz),7.70(1H, d, J=2 Hz), 7.93 (1H, dd. J=8.2 Hz), 8.04(1H, d J=2 Hz),8.45 (1H, d. J=2 Hz): m/z(API)⁺: 349 (MH+)

EXAMPLE 15

[0260]N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-bromo-4-methylbenzamideHydrochloride

[0261]¹H NMR [free base] (250 MHz: CD₃OD) 6: 1.23 (6H, s), 2.32.2.33(2×3H, s), 2.45 (2H. s)3.44 (2H, s), 7.30 (1H, d, J=8 Hz), 7.72 (1H, dd.J=8.2 Hz), 7.79 (1H, d, J=2 Hz), 8.02 (1H, d, J=2 Hz), 8.56 (1H, d, J=2Hz): m/z (API⁻):386.0, 387.9 (M−H)⁻.

EXAMPLE 16

[0262]N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-pivaloylbenzamide

[0263]¹H NMR (250 MHz: CDCl₃) δ: 1.36 (6H, s), 1.38 (9H, s), 2.45 (3H,s), 2.52 (2H, s), 3.59 (2H, s), 7.55 (1H, t, J=8 Hz), 7.88 (1H, m), 7.97(2H, m), 8.17 (1H, s), 8.44 (1H, d, J=2 Hz); m/z (API⁺): 380.4 (MH⁺:30%).

EXAMPLE 17

[0264]N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-5-chloro-2-methoxy-4-iso-propyloxybenzamideHydrochloride ¹H NMR [free base] (250 MHz: CDCl₃) S: 1.35 (6H, s), 1.44(6H, d. J=6 Hz), 2.44 (3H. s), 2.51 (2H, s), 3.37 (2H, s), 4.05 (3H, s),4.66 (1H, m), 6.57 (1H, s), 8.06 (1H, d, J=2 Hz), 8.26 (1H, s), 8.34(1H, d, J=2 Hz); m/z (API⁺): 416.1, 418.2 (M+H])⁺.

EXAMPLE 18

[0265]N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-cyano-4-ethoxybenzamideHydrochloride

[0266]¹H NMR [free base] (250 MHz: CD₃OD) δ: 1.27 (6H, s), 1.42 (3H, t,J=7 Hz), 2.37 (3H, s), 0.50 (2H, s), 3.52 (2H, s) 4.22 (2H, q, J=7 Hz),7.22 (1H, d, J=9 Hz), 7.84 (1H, d, J=2 Hz), 8.16 (2H, m), 8.60 (1H, d,J=2 Hz): m/z (API⁺): 365.1 (M+H)⁺.

EXAMPLE 19

[0267]N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-4-methoxy-3-trifluoroacetylbenzamide

[0268]¹H NMR (250 MHz; CDCl₃) δ: 1.34 (6H, s), 2.44 (3H, s), 2.51 (2H,s), 3.55 (2H, s), 3.99 (3H, s), 7.10(1H, d, J=8 Hz), 7.93 (1H, d, J=8Hz), 8.23 (2H, brm), 8.44(1H, brs), 8.51 (1H, d. J=2 Hz); m/z (API⁺):422.1 (MH⁺; 100%).

EXAMPLE 20

[0269]N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)naphthalene-2-carboxamide

[0270]¹H NMR (250 MHz: CDCl₃) δ: 1.42 (6H, s), 2.61 (3H, s), 2.76 (2H,s), 3.78 (2H, s), 7.20 (1H, m), 7.50-8.65 (7H, m), 7.95 (1H, d, J=2 Hz),8.46 (1H, s), 8.72 (1H, d, J=2 Hz); m/z (API⁺): 346.1 (MH⁺: 70%).

EXAMPLE 21

[0271] N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-cyano-4-iso-propyloxybenzamide Hydrochloride

[0272]¹H NMR[free base] (250 MHz:CD₃OD) δ: 1.24 (6H, s), 1.32 (6H, d,J=6 Hz), 2.34 (3H, s), 2.48 (2H, s), 3.49 (2H, s), 4.74-4.84 (1H, m),7.21 (1H, d, J=9 Hz), 7.81 (1H, d, J=2 Hz), 8.10 ([H, dd. J=9.2 Hz),8.14 (1H, d. J=2 Hz), 8.57(1H, d, J=2 Hz); m/z(API⁺): 379.2 (MH⁺)

EXAMPLE 22

[0273]N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-acetyl-4-ethylbenzamideHydrochloride

[0274]¹H NMR [free base] (250 MHz; CD₃OD) δ: 0.98 (3H, t, J=7 Hz), 1.11(6H, s), 2.20 (3H. s), 2.34 (2H, s), 2.41 (3H, s), 2.67 (2H, q, J=7 Hz),3.34 (2H, s), 7.22 (1H, brd. J=8 Hz), 7.70 (1H, brs), 7.78 (1H, brd. J=8Hz), 8.08 (1H, brs), 8.47 (1h, brs); m/z (API⁺): 366.2 (MH⁺)

EXAMPLE 23

[0275]N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-2,3-dihydrobenzofuran-5-carboxamideHydrochloride.

[0276] 1H NMR [free base] (250 MHz:CD₃OD) δ: 1.35 (6H, s) 2.44(3H, s),2.58 (2H, s), 3.26 (2H, t, J=9 Hz), 3.58(2H, s), 4.64 (2H, t, J=9 Hz),6.81 (1H, d, J=8 Hz), 7.76 (1H, dd. J=8.2 Hz), 7.83 (1H, brs), 7.89 (1H,d, J=2 Hz), 8.67(1H, d, J=2 Hz): m/z (API⁺): 338.2 (MH⁺)

EXAMPLE 24

[0277]N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-n-butyroyl-4-methoxybenzamideHydrochloride.

[0278]¹H NMR [free base] (250 MHz; CD₃OD) δ: 0.71 (3H, t, J=7 Hz),1.08(6H, s), 1.42 (2H, m), 2.17(3H, s), 2.31 (2H, s), 2.72 (2H, t, J=7Hz), 3.32 (2H, s), 3.74 (3H, s), 7.00 (1H, d, J=9 Hz), 7.64 (1H, m),7.86(1H, dd. J=9.2 Hz), 7.95 (1H, d, J=2 Hz), 8.41 (1H, d, J=2 Hz),m/z(API⁺): 396.2 (MH⁺), 418.2 (M+Na⁺).

EXAMPLE 25

[0279]N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-4-methoxy-3-n-propionylbenzamideHydrochloride.

[0280]¹H NMR [free base] (250 MHz; CD₃OD) δ:1.12 (3H, t, J=7 Hz), 1.31(6H, s), 2.41 (3H, s), 2.54 (2H, s), 3.00 (2H, q, J=7 Hz), 3.56 (2H, s),3.97 (3H, s), 7.24 (11H, d, J=9 Hz), 7.88 (1H, d, J=2 Hz) 8.10(1H, dd.J=9.2 Hz), 8.21(1H, d. J=2 Hz), 8.64(1H, d, J=2 Hz); m/z (API⁺): 382.2(MH⁺).

EXAMPLE 26

[0281]N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl-iso-butyroyl-4-methoxybenzamideHydrochloride.

[0282]¹H NMR [free base] (250 MHz;CD₃OD):1.04 (6H, d. 7 Hz), 1.25 (6H,s), 2.36(3H, s) 2.76 (2H, s), 3.40 (1H, m), 3.51 (2H, s), 3.88 (3H, s),7.15 (1H, d, J=8 Hz), 7.82 (1H, d, J=2 Hz), 8.02 (2H, m), 8.58 (1H, d,J=2 Hz): m/z (API⁺): 396.3 (MH⁺).

EXAMPLE 27

[0283]N-(8,8-Dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-ethoxy-3-trifluoromethylbenzamideHydrochloride.

[0284]¹H NMR [HCl salt] (250 MHz:CD₃OD) δ:1.53 (3H, t, J=7 Hz), 1.69(6H,s), 3.64 (2H, s), 4.35 (2H, q, J=7 Hz), 4.71 (2H, s), 7.41 (1H, d, J=9Hz), 8.38 (2H, m), 8.70 (1H, d. J=2 Hz), 9.38 (1H, d, J=2 Hz): m/z(API⁻): 364 1 [M−Et].

EXAMPLE 28

[0285]N-(8,8-Dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-acetyl-4-iso-propyloxybenzamideHydrochloride.

[0286]¹H NMR [free base] (250 MHz: CD₃OD) δ: 1.22 (6H, s), 1.34 (6H, d,J=6 Hz), 2.53 (3H, s), 2.84 (2H, s), 3.78 (2H, s), 4.76-4.86 (1H, m),7.15 (1H, d, J=9 Hz), 7.79 (1H, d. J=2 Hz), 7.99 (1H, dd. J=9. Hz), 8.18(1H, d, J=2 Hz), 8.57(1H, d, J=Hz): m/z (API⁺): 382.2 (MH⁺).

EXAMPLE 29

[0287]N-(8,8-Dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-bromo-4-methoxybenzamideHydrochloride.

[0288]¹H NMR [HCl salt] (250 MHz:(CD₃)₂SO): 1.27 (6H, s), 3.19 (2H,brs), 3.81 (3H, s), 4.22 (2H, brs), 7.14 (1H, d, J=9 Hz), 7.94(1H,brdd), 8.08(1H, brd), 8.14 (1H, d, J=2 Hz), 8.73 (1H, brd), 9.45-9.70(2H, brs, exchangeable), 10.53 (1H, brs, exchangeable); m/z (API⁻):389.8, 387.9 (M−H).

EXAMPLE 30

[0289] N-(8,8-Dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-chloro-4-methoxybenzamide Hydrochloride.

[0290]¹H NMR [HCl salt] (250 MHz: (CD₃)₂SO) δ: 1.40 (6H, s), 3.30 (2H,brs), 3.91 (3H, s). 4.33 (214, brs), 7.28(1H, d, J=8 Hz), 8.02(1H, dd.J=9.2 Hz), 8.11 (1H, d, J=2 Hz). 8.25 (1H, d, J=2 Hz), 8.88 (1H, d, J=2Hz), 9.85 (2H, brs, exchangeable), 10.73 (1H, s. exchangeable): m/z(API⁺): 346.1, 347.2 (MH⁺: 100%)

EXAMPLE 31

[0291]N-(8,8-Dimethyl-3,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-methoxy-3-pentafluoroethylBenzamide

[0292]¹H NMR (400 MHz. CDCl,) a: 1.32 (6H, s), 2.96 (2H, s), 3.96 (3H,s), 4.05 (2H, s), 7.13 (1H, d), 7.93 (1H, s), 8.04 (1H, s), 8.06(1H, s),8.44((1H, d): m/z (API +): 430 (M+H)⁺

EXAMPLE 32

[0293]N-(8,8-Dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-iso-propoxy-3-trifluoromethylBenzamide

[0294]¹H NMR (400 MHz. CD₃OD) δ: 1.41 (6H, d, J=6 Hz), 1.70 (6H, s),3.63 (2H, s), 4.71 (2H, s), 4.95 (1H, m—overlapped by solvent), 7.40(1H, d), 8.32 (1H, s), 8.34 (1H, d), 8.73 (1H, s), 9.45 (1H, s); m/z(API+): 408 (M+H)

EXAMPLE 33

[0295]N-(8,8-Dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-ethyl-3-trifluoromethylBenzamide

[0296]¹H NMR (400 MHz. CD₃OD) δ: 1.35 (3H, t, J=7 Hz), 1.62 (6H, s),2.96 (2H, q), 3.57 (2H, s), 4.63 (2H, s), 7.68 (1H, d), 8.25 (1H, d),8.33 (1H, s), 8.57 (1H, s), 9.21 (1H, s). m/z (API+): 378 (M+H)⁺

EXAMPLE 34

[0297]N-(8,8-Dimethyl-5,6,7,8-tetrahydrol[1,6]naphthyridin-3-yl)-3-bromo-4-iso-propylBenzamide

[0298]¹H NMR (400 MHz. CD₃OD) δ: 1.32 (6H, d, J=6 Hz), 1.65 (6H, s),3.50 (1H, m), 3.59 (2H, s), 4.67 (2H, s), 7.58 (1H, d), 8.02 (1H, d),8.26 (1H, s), 8.63 (1H, s), 9.32 (1H, s): m/z (API⁺): 402, 404 (M+H)⁺

EXAMPLE 35

[0299] N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-chloro-4-ethoxybenzamide

[0300]¹H NMR (250 MHz: CDCl₃) δ: 1.36 (6H, s), 1.52 (3H, t, J=7 Hz),2.45 (3H, s), 2.53 (2H, s), 3.59 (2H, s), 4.19(2H, q, J=7 Hz), 7.00(1H,d, J=7 Hz), 7.64(1H, brs), 7.76 (1H, dd. J=7,2 Hz), 7.90 (1H, d, J=2Hz), 7.98(1H, d, J=2 Hz), 8.42(1H, d, J=2 Hz); m/z (API⁺): 396.2 (M+Na⁺,100%), 374.2 (MH⁺: 33%).

EXAMPLE 36

[0301]N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-fluoro-4-methoxybenzamide

[0302]¹H NMR (400 MHz: CDCl,) δ: 1.35 (6H, s), 2.44 (3H, s), 2.50 (2H,s), 3.56 (2H, s), 3.99 (3H, s), 7.03 (1H, t, J=7 Hz), 7.62 (1H, d), 7.72(1H, s), 7.95 (1H, d. J=2 Hz), 8.40 (1H. d, J=2 Hz); m/z (API⁺): 344.2(MH⁺; 93%).

EXAMPLE 37

[0303] N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-4-methoxy-3-pentafluoroethylbenzamide

[0304]¹H NMR (400 MHz; CDCl₃) δ: 1.35 (6H, s), 2.46 (3H, s), 2.51 (2H,s), 3.57 (2H, s), 3.96 (3H, s), 7.10(1H, d. J=7 Hz), 7.71 (1H, s),7.93(1H, d. J=2 Hz), 8.04 (1H, d), 8.06 (1H, d), 8.44 (1H, d, J=2 Hz);m/z (API⁺): 444 (MH⁺; 90%).

EXAMPLE 38

[0305]N-(8,8-Dimethyl-5,6,7,8-tetrahydro[1,6πnaphthyridin-3-yl)-3-fluoro-4-methoxybenzamideHydrochloride.

[0306]¹H NMR (250 MHz; CDCl₃) [free base] δ: 1.32 (6H, s), 2.20 (2H, s),3.07 (2H, s), 3.96 (3H, s), 4.04 (2H, s), 7.02 (1H, t, J=7 Hz), 7.62(1H, d), 7.64 (1H, d), 7.95 (1H, d, J=2 Hz), 8.44 (1H, d, J=2 Hz); m/z(API⁺): 330 (MH⁺; 100%).

EXAMPLE 39

[0307]N-(8,8-Dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-methoxy-3-propionylbenzamide.

[0308]¹H NMR (250 MHz; CDCl₃) δ: 1.18 (3H, t, J=7 Hz), 1.32 (6H, s),2.96 (2H, s), 3.05 (2H, q. J=7 Hz), 3.99(31H, s), 4.05(2H, s), 7.11 (1H,d. J=7 Hz), 7.97 (1H, d. J=2 Hz), 8.11 (2H, d), 8.16 (1H, d), 8.45 (1H,d); m/z (API⁺): 390 (MNa⁺: 93%), 368 (MH⁺ 80%)

EXAMPLE 40

[0309]N-(5,6,7,8-Tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-indole-2-carboxamide.

[0310]¹H NMR (250 MHz: CDCl₃ +CD₃OD) δ: 1.34 (6H, s), 2.46 (3H, s), 2.56(2H, s), 3.60 (2H, s), 7.20-7.90(6H, m), 8.12(1H, d, J=2 Hz), 8.40 (1H,d, J 2 Hz), 8.60(1H, brd, J=8 Hz); m/z (API⁺): 335.2 (MH⁺: 100%)

[0311] Pharmacological Data

[0312] 1. Binding Assay Method

[0313] WO 92!22293 (SmithKline Beecham) discloses compounds havinganti-convulsant activity including inter alia the compoundtrans-(+)-6-acetyl-4S-(4-fluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3R-ol(hereinafter referred to as Compound A). It has been found that thecompounds of WO 92/22293 bind to a novel receptor obtainable from ratforebrain tissue, as described in WO 96/18650 (SmithKline Beecham). Theaffinity of test compounds to the novel receptor site is assessed asfollows.

[0314] Method

[0315] Whole forebrain tissue is obtained from rats. The tissue is firsthomogenised in buffer (usually 50 mM Tris/HCl, pH 7.4). The homogenisedtissue is washed by centrifugation and resuspension in the same buffer,then stored at −70° C. until used.

[0316] To carry out the radioligand binding assay, aliquots of tissueprepared as above (usually at a concentration of 1-2 mg protein/ml) aremixed with aliquots of [3H]-Compound A dissolved in buffer. The finalconcentration of [3H]-Compound A in the mixture is usually 20 nM. Themixture is incubated at room temperature for 1 hour. (3H]-Compound Abound to the tissue is then separated from unbound [3H]-Compound A byfiltration through Whatman GF/B glass fibre filters. The filters arethen washed rapidly with ice-cold buffer. The amount of radioactivitybound to the tissue trapped on the filters is measured by addition ofliquid scintillation cocktail to the filters followed by counting in aliquid scintillation counter.

[0317] In order to determine the amount of “specific” binding of[3H]-Compound A, parallel assays are carried out as above in which[3H]-Compound A and tissue are incubated together in the presence ofunlabelled Compound A (usually 3 μM). The amount of binding of[3H]-Compound A remaining in the presence of this unlabelled compound isdefined as “non-specific” binding. This amount is subtracted from thetotal amount of [3H]-Compound A binding (i.e. that present in theabsence of unlabelled compound) to obtain the amount of “specific”binding of [3H]-Compound A to the novel site.

[0318] The affinity of the binding of test compounds to the novel sitecan be estimated by incubating together [3]-Compound A and tissue in thepresence of a range of concentrations of the compound to be tested. Thedecrease in the level of specific [3H]-Compound A binding as a result ofcompetition by increasing concentrations of the compound under test isplotted graphically, and non-linear regression analysis of the resultantcurve is used to provide an estimate of compound affinity in terms ofpKi value.

[0319] Results

[0320] Compounds of this invention were active in this test with pKi>6.For example, compounds of Examples 2-11 and 25-34 gave pKi valuesgreater than 8.

[0321] 2. MEST Test

[0322] The maximal electroshock seizure (MEST) threshold test in rodentsis particularly sensitive for detecting potential anticonvulsantproperties¹. In this model, anticonvulsant agents elevate the thresholdto electrically-induced seizures whilst proconvulsants lower the seizurethreshold.

[0323] Method for Mouse Model

[0324] Mice (naive male. Charles River. U.K. CD-1 strain. 25-30 g) arerandomly assigned to groups of 10-20 and dosed orally orintraperitoneally at a dose volume of 10 ml/kg with various doses ofcompound (0.3-300 mg/kg) or vehicle. Mice are then subjected at 30 or 60min post dose to a single electroshock (0.1 sec. 50 Hz, sine wave form)administered via corneal electrodes. The mean current and standard errorrequired to induce a tonic seizure in 50% (CC₅₀) of the mice in aparticular treatment group is determined by the ‘up and down’ method ofDixon and Mood (1948)². Statistical comparisons between vehicle- anddrug-treated groups are made using the method of Litchfield and Wilcoxon(1949)³.

[0325] In control animals the CC₅₀ is usually 14-18 mA. Hence the firstanimal in the control group is subjected to a current of 16 mA. If atonic seizure does not ensue, the current is increased for a subsequentmouse. If a tonic convulsion does occur, then the current is decreased,and so on until all the animals in the group have been tested.

[0326] Studies are carried out using a Hugo Sachs Electronik ConstantCurrent Shock Generator with totally variable control of shock levelfrom 0 to 300 mA and steps of 2 mA are usually used.

[0327] Method for Rat Model

[0328] The threshold for maximal (tonic hindlimb extension) electroshockseizures in male rats (Sprague Dawley. 80-150 g. 6 weeks old) wasdetermined by a Hugo Sachs Electronik stimulator which delivered aconstant current (0.3 sec duration; from 1-300 mA in steps of 5-20 mA).The procedure is similar to that outlined above for mouse and fulldetails are as published by Upton et al,.⁴

[0329] The percentage increase or decrease in CC₅₀ for each groupcompared to the control is calculated.

[0330] Drugs are suspended in 1% methyl cellulose.

[0331] Results

[0332] At a dosage of 2 mg/kg p.o. at 2 h. the compounds of Examples 3and 5 showed increases in the rat model of 314% and 350% respectively.

[0333] References

[0334] 1. Loscher, W. and Schmidt. D. (1988). Epilepsy Res. 2. 145-181

[0335] 2. Dixon, W. J. and Mood. A. M. (1948). J. Amer. Stat. Assn. 43,109-126

[0336] 3. Litchfield, J. T. and Wilcoxon, F.(1949). J. Pharmacol. exp.Ther. 96. 99-113

[0337] 4. N. Upton. T. P. Blackburn, C. A. Campbell, D. Cooper, M. L.Evans, H. J. Herdon., P. D. King, A. M. Ray, T. O. Stean. W. N. Chan. J.M. Evans and M. Thompson. (1997). B. J. Pharmacol., 121. 1679-1686

1. A compound of formula (I) or a pharmaceutically acceptable salt orsolvate thereof:

where R¹ is hydrogen. C₁₋₆alkyl (optionally substituted by hydroxy orC₁₋₄alkoxy), phenyl-C₁₋₄alkyl-, C₁₋₆alkenyl, or C₁₋₆alkynyl; R² ishydrogen or up to three substituents selected from halogen.NO_(2, CN, N) ₃, CF₃O—, CF₃S—, CF₃SO₂—, CF₃CO—, C₁₋₆alkyl, C₁₋₆alkenyl,C₁₋₆alkynyl. C₁₋₆perfluoroalkyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkyl-C₁₋₄alkyl-, C₁₋₆alkylO—, C₁₋₆alkylCO—, C₃₋₆cycloalkylO—,C₃₋₆cycloalkylCO—, C₃₋₆cycloalkyl-C₄alkylO—,C₃₋₆cycloalkyl-C₁₋₄alkylCO—, phenyl, phenoxy, benzyloxy, benzoyl,phenyl-C₁₋₄alkyl-, C₁₋₆alkylS—, C₁₋₆alkylSO₂—, (C₁₋₄alkyl)₂NSO₂—,(C₁₋₄alkyl)NHSO₂—, (C₁₋₄alkyl)2NCO—, (C₁₋₄alkyl)NHCO— or CONH₂; or—NR⁵R⁶ where R⁵ is hydrogen or C₁₋₄ alkyl, and R⁶ is hydrogen,C₁₋₄alkyl, formyl, —CO₂C₁₋₄alkyl or —COCl₁₋₄alkyl; or two R² groupstogether form a carbocyclic ring that is saturated or unsaturated,optionally interrupted by O or NH; R³ groups and R⁴ groups are eachindependently hydrogen or C₁₋₆ alkyl and/or the two R³ groups and/or thetwo R⁴ groups together form a C₃₋₆ spiroalkyl group, provided that atleast one R³ or R⁴ group is not hydrogen; and is selected from hydrogen,halogen, cyano, alkyl and alkoxy.
 2. A compound according to claim 1 offormula (IA)


3. A compound according to claim 1 of formula (IB)


4. A compound selected from the group consisting of.N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)benzamide;N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-cyano-4-iso-propylbenzamide:N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-4-methoxy-3-trifluoromethylbenzamide:N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-bromo-4-ethylbenzamide;N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-bromo-4-ethoxybenzamide;N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-chloro-4-iso-propyloxybenzamide;N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-bromo-4-iso-propyloxybenzamide;N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-acetyl-4-iso-propyloxybenzamide;N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-4-ethoxy-3-trifluoromethylbenzamide;N-(8,8-dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-methoxy-3-trifluoromethylbenzamide;N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-bromo-4-methoxybenzamide;N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-chloro-4-methoxybenzamide;N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-cyano-4-methoxybenzamide;N-(5,6,7,8-tetrahydo-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-cyano-4-ethylbenzamide.N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-bromo-4-methylbenzamide;N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-pivaloylbenzamide;N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-5-chloro-2-methoxy-4-iso-propytoxybenzamide;N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-cyano-4-ethoxybenzamide;N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-4-methoxy-3-trifluoroacetylbenzamide;N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)naphthalene-2-carboxamide;N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-cyano-4-iso-propyloxybenzamide:N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-acetyl-4-ethylbenzamide:N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-2,3-dihydrobenzofuran-5-carboxamide;N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-n-butyroyl-4-methoxybenzamide;N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)4-methoxy-3-n-propionylbenzamide;N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl-iso-butyroyl-4-methoxybenzamide;N-(8,8-dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-ethoxy-3-trifluoromethylbenzamide;N-(8,8-dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-acetyl-4-iso-propyloxybenzamide:N-(8,8-dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-bromo-4-methoxybenzamide;N-(8,8-dimethyl-5,6,7,8-tetrahydro [1,6]naphthyridin-3-yl)-3-chloro-4-methoxybenzamide;N-(8,8-dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-methoxy-3-pentafluoroethylbenzamide; N-(8,8-dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-iso-propoxy-3-trifluoromethyl benzamide;N-(8,8-dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-ethyl-3-trifluoromethyl benzamide;N-(8,8-dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-bromo-4-iso-propyl benzamide;N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-chloro-4-ethoxybenzamide,N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-fluoro-4-methoxybenzamide;N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-4-methoxy-3-pentafluoroethylbenzamide;N-(8,8-dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-fluoro-4-methoxybenzamide;N-(8,8-dimethyl-5,6,7,8-tetrahydro [1,6]naphthyridin-3-yl)-4-methoxy-3-propionylbenzamide, and;N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-indole-2-carboxamide.5. A pharmaceutical composition for use in the treatment and/orprophylaxis of anxiety, mania, depression, panic disorders and/oraggression, disorders associated with a subarachnoid haemorrhage orneural shock, the effects associated with withdrawal from substances ofabuse such as cocaine, nicotine, alcohol and benzodiazepines, disorderstreatable and/or preventable with anti-convulsive agents, such asepilepsy including post-traumatic epilepsy, Parkinson's disease,psychosis, migraine, cerebral ischaemia, Alzheimer's disease and otherdegenerative diseases such as Huntingdon's chorea, schizophrenia,obsessive compulsive disorders (OCD), neurological deficits associatedwith AIDS, sleep disorders (including circadian rhythm disorders,insomnia & narcolepsy), tics (e.g. Giles de la Tourette's syndrome),traumatic brain injury, tinnitus neuralgia, especially trigeminalneuralgia, neuropathic pain, dental pain, cancer pain, inappropriateneuronal activity resulting in neurodysthesias in diseases such asdiabetes, multiple sclerosis (MS) and motor neurone disease, ataxias,muscular rigidity (spasticity), temporomandibular joint dysfunction, andamyotrophic lateral sclerosis (ALS) which comprises a compound accordingto any one of the preceding claims and a pharmaceutically acceptablecarrier.
 6. A method of treatment and/or prophylaxis of anxiety, mania,depression, panic disorders and/or aggression, disorders associated witha subarachnoid haemorrhage or neural shock, the effects associated withwithdrawal from substances of abuse such as cocaine, nicotine, alcoholand benzodiazepines, disorders treatable and/or preventable withanti-convulsive agents, such as epilepsy including post-traumaticepilepsy, Parkinson's disease, psychosis, migraine, cerebral ischaemia,Alzheimer's disease and other degenerative diseases such as Huntingdon'schorea, schizophrenia, obsessive compulsive disorders (OCD),neurological deficits associated with AIDS, sleep disorders (includingcircadian rhythm disorders, insomnia & narcolepsy), tics (e.g. Giles dela Tourette's syndrome), traumatic brain injury, tinnitus, neuralgia,especially trigeminal neuralgia, neuropathic pain, dental pain, cancerpain, inappropriate neuronal activity resulting in neurodysthesias indiseases such as diabetes, multiple sclerosis (MS) and motor neuronedisease, ataxias, muscular rigidity (spasticity), temporomandibularjoint dysfunction, and amyotrophic lateral sclerosis (ALS) comprisingadministering to the sufferer in need thereof an effective orprophylactic amount of a compound according to any one of claims 1 to 4.7. Use of a compound according to any one of claims 1 to 4, for themanufacture of a medicament for the treatment and/or prophylaxis ofanxiety, mania, depression, panic disorders and/or aggression, disordersassociated with a subarachnoid haemorrhage or neural shock, the effectsassociated with withdrawal from substances of abuse such as cocaine,nicotine, alcohol and benzodiazepines, disorders treatable and/orpreventable with anti-convulsive agents, such as epilepsy includingpost-traumatic epilepsy, Parkinson's disease, psychosis, migraine,cerebral ischaemia, Alzheimer's disease and other degenerative diseasessuch as Huntingdon's chorea, schizophrenia, obsessive compulsivedisorders (OCD), neurological deficits associated with AIDS, sleepdisorders (including circadian rhythm disorders, insomnia & narcolepsy),tics (e.g. Giles de la Tourette's syndrome), traumatic brain injury,tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain,dental pain, cancer pain, inappropriate neuronal activity resulting inneurodysthesias in diseases such as diabetes, multiple sclerosis (MS)and motor neurone disease, ataxias, muscular rigidity (spasticity),temporomandibular joint dysfunction, and amyotrophic lateral sclerosis(ALS).
 8. A process for the preparation of compounds according to anyone of claims 1 to 4 which comprises reacting a compound of formula (II)

where R^(1A), R^(3A), R^(4A), X are R¹, R³, R⁴, X as defined for formula(I) or a group or groups convertible to R¹, R³, R⁴, X with a compound offormula (III)

where Y is a leaving group, and R^(2A) groups are independently R² asdefined for formula (I) or a group or groups convertible to R², andwhere required converting an R^(1A), R^(2A), R^(3A), R^(4A), X group toa R¹, R², R³, R⁴, X group, converting one R¹, R², R³, R⁴, X group toanother R¹, R², R³, R⁴, X group, or converting a salt product to thefree base or another pharmaceutically acceptable salt, or separating anyenantiomers, or converting a free base product to a pharmaceuticallyacceptable salt.